Human degenerative neurological disorders are often characterized by progressive loss of specific neuronal populations or systems. Our understanding of these diseases, including inherited ataxias, Alzheimer's disease (AD), neuraxonal dystrophy, and motor neuron disease, has been slowed because of lack of models for investigation. Discussions with veterinarians and review of the literature disclose that many animal disorders resemble human diseases, but too frequently they are not exploited for investigation. Animal models are particularly useful for studying degenerative processes: nerve cell-specific pathology can be identified; the evolution of the disease process can be assessed at various stages; the consequences of abnormalities in one nerve cell group on other neuronal systems can be analyzed; and, therapeutic approaches can be tested before use in human patients. The Principal Investigator (PI) has a longstanding commitment to the identification, development, and investigation of animal models of human disease including: motor neuron disease, cerebellar ataxia, lysosomal storage disease, demyelinating disease, and AD. The present proposal describes plans to study three animal models involving different neuronal populations: Canine Inherited Ataxia (CIA) (cerebellar systems); Canine Neuroaxonal Dystrophy (CNAD) (sensory afferents and other pathways); and, Pallidonigral Degeneration in Monkeys (PND). In each model morphometric and ultrastructural methods will be used to examine the type, distribution and time course of the pathology and these abnormalities will be correlated with the density and distribution of markers (e.g., receptors) associated with specific populations of nerve cells. This approach will allow documentation of primary and secondary abnormalities of specific systems during the progression of disease. In addition, in CNAD, because the conspicuous distal axonal pathology suggests an abnormality of axonal transport, the PI will utilize techniques similar to those successfully used to study Hereditary Canine Spinal Muscular Atrophy, an animal model of motor neuron disease. Finally, the PI will continue to search for, identify, develop, and investigate other animal models of degenerative neurological disease. Investigations of these models may ultimately contribute to the design and testing of therapeutic strategies for human patients.